Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia

• Matsuo, Hidemasa

• Yoshida, Kenichi

• Fukumura, Kazutaka

• Nakatani, Kana

• Noguchi, Yuki

• Takasaki, Saho

• Noura, Mina

• Shiozawa, Yusuke

• Shiraishi, Yuichi

• Chiba, Kenichi

• Tanaka, Hiroko

• Okada, Ai

• Nannya, Yasuhito

• Takeda, June

• Ueno, Hiroo

• Shiba, Norio

• Yamato, Genki

• Handa, Hiroshi

• Ono, Yuichiro

• Hiramoto, Nobuhiro

• Ishikawa, Takayuki

• Usuki, Kensuke

• Ishiyama, Ken

• Miyawaki, Shuichi

• Itonaga, Hidehiro

• Miyazaki, Yasushi

• Kawamura, Machiko

• Yamaguchi, Hiroki

• Kiyokawa, Nobutaka

• Tomizawa, Daisuke

• Taga, Takashi

• Tawa, Akio

• Hayashi, Yasuhide

• Mano, Hiroyuki

• Miyano, Satoru

• Kamikubo, Yasuhiko

• Ogawa, Seishi

• Adachi, Souichi

Abstract

In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3–rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.

Journal

• Blood Advances

  Blood Advances 2 (21), 2879-2889, 2018-11-13

  American Society of Hematology

Keywords

• Hematology

Details

• CRID: 1050845763220910336
• NII Article ID: 120006534600
• ISSN: 24739529
• ISSN: 24739537
• DOI: 10.1182/bloodadvances.2018019398
• HANDLE: 2433/234946
• Web Site: http://ashpublications.org/bloodadvances/article-pdf/2/21/2879/1629845/advances019398.pdf
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN